Characterization of endothelium‐derived hyperpolarizing factor as a cytochrome P450‐derived arachidonic acid metabolite in mammals.

Hecker, Markus; Bara, Agnieszka T.; Bauersachs, Johann; Busse, Rudi

doi:10.1113/jphysiol.1994.sp020449

Cited by 394 publications

(337 citation statements)

References 22 publications

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“…The mono-oxygenases themselves seem to be located primarily within the endothelium (Abraham et al, 1985) and endothelial cells are capable of synthesizing EETs (see Harder et al, 1995). These findings, together with the ability of cytochrome P450 inhibitors, such as proadifen and clotrimazole, to attenuate EDHF-mediated vasodilatation, support the view that EDHF is an arachidonic acid metabolite derived via a cytochrome P450-dependent mono-oxygenase (Fulton et al, 1992;Bauersachs et al, 1994;Hecker et al, 1994;Lischke et al, 1995).…”

Section: Introductionsupporting

confidence: 67%

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Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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1 The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors No-nitro-L-arginine (L-NOARG) and indomethacin, respectively.2 17-Octadecynoic acid (17-ODYA, 50 gM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5, 8, 11,[12][13][14], had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 gM). Furthermore, 5, 8, 11, Clotrimazole (3 gM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 gM). 5 The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 gM) and strongly attenuated by clotrimazole (3 gM). Proadifen (10 gM) also abolished the hyperpolarization induced by levcromakalim (1 gM). 6 The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

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Section: Introductionsupporting

confidence: 67%

“…Certain metabolites of arachidonic acid such as 5,8,11,[12][13][14] can relax blood vessels (Pfister et al, 1991;Gebremedhin et al, 1992;Rosolowsky & Campbell, 1993;Hecker et al, 1994) and activate potassium (K) channels in vascular smooth muscle cells (Gebremedhin et al, 1992;Hu 1 Author for correspondence. & Kim, 1993).…”

Section: Introductionmentioning

confidence: 99%

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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“…17) For example, Ca 2＋ -activated K ＋ channels may be involved in bradykinin-induced dilation of bovine and porcine coronary arteries. 11) Other studies of rabbit cerebral arteries 3) have reported that GB inhibited hyperpolarization in response to acetylcholine. This study did not examine the effect of other K ＋ -channel subtype inhibitors in bFGF-induced hyperpolarization, and therefore we could not exclude the possibility of their involvement in this response.…”

Section: Discussionmentioning

confidence: 99%

Vasodilatory Effect of Basic Fibroblast Growth Factor in Isolated Rat Cerebral Arterioles: Mechanisms Involving Nitric Oxide and Membrane Hyperpolarization.

Kajita

Takayasu²,

Yoshida³

et al. 2001

Neurol. Med. Chir.(Tokyo)

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Basic fibroblast growth factor (bFGF), a potent mitogen, acutely dilates cerebral blood vessels and may be effective in reducing cerebral infarction. However, the vasodilatory mechanism, which may involve nitric oxide (NO), is not completely understood. This study investigated whether membrane hyperpolarization is also involved in this mechanism. Membrane potential (MP) of smooth muscle cells and vessel diameter of isolated intracerebral arterioles were simultaneously measured following extraluminal application of bFGF in rats. The involvement of NO and adenosine triphosphate-sensitive potassium (K ATP ) channels in bFGF-induced vasodilation and membrane hyperpolarization was evaluated using specific inhibitors, N G -monomethyl-L-arginine (L-NMMA, 10 -4 M) and glibenclamide (GB, 10 -5 M), respectively. The resting MP was recorded at a mean value of -31.9 ± 4.5 mV. bFGF (1 to 1000 ng/ml) produced significant vasodilation and hyperpolarization. Treatment with L-NMMA caused vasoconstriction and significantly attenuated bFGF-induced vasodilation without affecting membrane hyperpolarization. In the presence of GB, the membrane potential was significantly depolarized but the vessel diameter was only marginally reduced, so bFGF-induced membrane hyperpolarization was inhibited while arteriolar dilation was attenuated. These results suggest that bFGF-induced vasodilation is mediated by a mechanism involving both NO and membrane hyperpolarization, and that membrane hyperpolarization is caused by the activation of K ATP channels.

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“…The EETs induce vasodilation by opening Ca 2+ -activated K + (K Ca ) channels on the vascular smooth muscle cell, which increases K + influx and hyperpolarizes the cell membrane [19,46,50,51,54,[64][65][66]. It is thought that this hyperpolarization decreases Ca 2+ influx through voltage-sensitive Ca 2+ channels, ultimately leading to a decrease in intracellular [Ca 2+ ] with subsequent vasorelaxation, as shown in Fig.…”

Section: Vasomotor Actions Of Eetsmentioning

confidence: 99%

Emerging role of epoxyeicosatrienoic acids in coronary vascular function

Larsen

Gutterman

Hatoum

2006

Eur J Clin Investigation

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The importance of endothelium-derived nitric oxide in coronary vascular regulation is well-established and the loss of this vasodilator compound is associated with endothelial dysfunction, tissue hypoperfusion and atherosclerosis. Numerous studies indicate that the endothelium produces another class of compounds, the epoxyeicosatrienoic acids (EETs), which may partially compensate for the loss of nitric oxide in cardiovascular disease. The EETs are endogenous lipids which are derived through the metabolism of arachidonic acid by cytochrome P450 epoxygenase enzymes. Also, EETs hyperpolarize vascular smooth muscle and induce dilation of coronary arteries and arterioles, and therefore may be endogenous mediators of coronary vasomotor tone and myocardial perfusion. In addition, EETs have been shown to inhibit vascular smooth muscle migration, decrease inflammation, inhibit platelet aggregation and decrease adhesion molecule expression, therefore representing an endogenous protective mechanism against atherosclerosis. Endogenous EETs are degraded to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase. Pharmacological inhibition of soluble epoxide hydrolase has received considerable attention as a potential approach to enhance EET-mediated vascular protection, and several compounds have appeared promising in recent animal studies. The present review discusses the emerging role of EETs in coronary vascular function, as well as recent advancements in the development of pharmacological agents to enhance EET bioavailability.

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Characterization of endothelium‐derived hyperpolarizing factor as a cytochrome P450‐derived arachidonic acid metabolite in mammals.

Cited by 394 publications

References 22 publications

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Vasodilatory Effect of Basic Fibroblast Growth Factor in Isolated Rat Cerebral Arterioles: Mechanisms Involving Nitric Oxide and Membrane Hyperpolarization.

Emerging role of epoxyeicosatrienoic acids in coronary vascular function

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